Dr. Kristoffer Rem Labing-isa

1. Dr. Kristoffer Rem Labing-isa Massachusetts Institute of Technology

2. Nitro Group Structure N double bonded to O and also single bonded to O and to an R.

3. Background Often highly explosive, especially when the compound contains more than one nitro group. one of the most common explosophores (functional group that makes a compound explosive) used globally.

4. Background The NO2 group is called as nitro group. It is electron withdrawing group due to its -Inductive effect as well as -Resonance effect. The structure of NO2 group is given below.

5. Background Trinitrotoluene, best known as a useful explosive material with convenient handling properties

6. Nomenclature Name the longest and continuous carbon chain Name the –NO2 compound as a –nitro substituent Aliphatic Nitro Aromatic Nitro Nitromethane Nitrobenzene

7. Nomenclature Nitro butane 1-nitronaphthalene 2-methyl-3-nitrobutane

8. Physical Properties Aliphatic Nitro colorless liquids with pleasant smell, sparingly soluble in water, have high boiling points. Most of nitro alkanes are quite stable and can be distilled without decomposition, and they are polar due to the presence of nitro group

9. Physical Properties Aromatic Nitro yellow color liquids which intensified to brown by time color with characteristic odor, steam volatile and can be purified by steam distillation and they are polar due to the presence of nitro group

10. Chemical Properties Aliphatic Nitro Nitro compounds undergo tautomerism in solution to azinitro form, which is acidic in nature. Hence, all the nitro compounds are weakly acidic in nature.

11. Chemical Properties Aromatic Nitro Nitro benzene is electron withdrawing group by both inductive effect and resonance effect. Hence it deactivates the benzene ring and it is meta directing group.

12. Preparation By direct nitration of alkanes CH3-CH3 + HNO3/H2SO4 → CH3-CH2-NO2 ethane nitroethane benzene nitrobenzene

13. Preparation By treating amines with alkaline KMnO4 aminomethane nitromethane

14. Nitro Journal

15. α-Fluoro-α-nitro(phenylsulfonyl)methane as a fluoromethylpronucleophile: Efficient stereoselective Michael addition to chalcones G. K. Surya Prakash1, Fang Wang, Timothy Stewart, Thomas Mathew, and George A. Olah1

16. Introduction Enantioselective preparation of fluoromethylatedorganics is one of the major areas of interest today because fluoromethyl substituted compounds carry great importance in pharmaceutical chemistry, material science and healthcare

17. Introduction One of the major recent developments in this area involves the efficient, and highly enantioselectivemonofluoralkylation of alcohols using the Mitsunobu reaction

18. Introduction Our recent investigations showed that fluorine containing (phenylsulfonyl)methane derivatives such as -nitro, cyano, ester, or acetyl-substituted fluoro(phenylsulfonyl)methane can be effectively used under mild conditions for the synthesis of a variety of functionalized monofluoromethylatedcompounds, which are crucial synthons for many valuable compounds in the pharmaceutical arena

19. Introduction

20. Introduction Very recently, Shibata and colleagues have achieved a catalytic enantioselective Michael addition of FBSM to chalcones using cinchona-based phase transfer catalysts. Michael addition between nitromethane and chalcone with high ee and chemical yields using cinchona alkaloid-derived chiral bifunctionalthioureaasaneffective organocatalyst.

21. Introduction Preliminary screening of the catalysts was carried out using dichloromethane or toluene as solvent.

22. Introduction We have screened a series of catalysts for the enantioselective addition of -fluoro--nitro- (phenylsulfonyl)methane (FNSM) to chalocones systematically and we found that catalysts enable this reaction to occur successfully in the absence of any base to provide exclusive 1,4-addition products

23. Discussion

24. Introduction FNSM has been added to a series of chalconederivatives to obtain the corresponding adducts in high yields with high diastereomeric ratios and excellent enantiomeric excesses

25. Discussion The bifunctional catalysts themselves are capable of deprotonating the FNSM into the corresponding carbanion, which can attack the Michael acceptors in an appropriate configuration by undergoing an inversion

26. Discussion The absolute configuration of the product was unequivocally established by X-ray crystallographic analysis

27. Methods Typical Procedure for Catalytic 1,4-Addition of -Fluoro--nitro(phenylsulfonyl) methane to ,-Unsaturated Ketones. To a solution of -fluoro--nitro(phenylsulfonyl) methane (21.9 mg, 0.1 mmol, 1 equivalent) and ketone (0.2 mmol, 2 equivalent) in CH2Cl2, Et3N (10.0 L of 0.1 mmol, 0.7 equivalent) was added. The reaction mixture was stirred for 12 h at room temperature and the conversion was monitored by 19F NMR before purification (diastereomeric ratios were 1:1 in all of the cases). The reaction mixture was loaded on to a preparative TLC plate. In most cases, the diastereomers can be separated with hexane/ethyl acetate (4/1– 6/1) to produce the title product in good to excellent yield.

28. Methods Typical Procedure for Catalytic Enantioselective 1,4-Addition of -Fluoro--nitro- (phenylsulfonyl)methane to Chalcones. To a solution of -fluoro--nitro(phenylsulfonyl) methane (21.9 mg, 0.1 mmol, 1 equivalent) and ketone (0.2 mmol, 2 equivalent) in precooled toluene (20 °C, 0.5 mL), catalystQNI was added (6.0 mg, 0.01 mmol, 10 mol%) in one load. The reaction mixture was stirred for 1 min and placed in freezer (20 °C) for 2 days without stirring. The reaction mixture was monitored by 19F NMR for conversion and diastereoselectivity, and loaded on to preparative TLC plate. In most cases, the diastereomerscan be separated with hexane/ethyl acetate (4/1– 6/1) to produce the title product in good to excellent yield. Products were characterized by spectral analysis (1H NMR, 13C NMR, 19F NMR, and HRMS), and the ee values were determined by chiral HPLC.

29. Conclusion In conclusion, we have achieved an enantioselective and diastereoselective 1,4-conjugate addition of FNSM, an effective fluoromethylpronucleophileto chalcones using cinchona alkaloid based bifunctionalcatalysts with highest efficacy observed for QN I.